Glucose is a simple sugar used by all the cells of the body to produce energy and support life. Humans need a minimum level of glucose in their blood at all times to stay alive. The primary manner in which the body produces blood glucose is through the digestion of food. When a person is not getting sufficient glucose from food digestion, glucose is produced from stores in the tissue and released by the liver. The body's glucose levels are primarily regulated by insulin. Insulin is a peptide hormone that is naturally secreted by the pancreas. Insulin helps glucose enter the body's cells to provide a vital source of energy.
When a healthy individual begins a meal, the pancreas releases a natural spike of insulin called the first-phase insulin release. In addition to providing sufficient insulin to process the glucose entering the blood from digestion of the meal, the first-phase insulin release acts as a signal to the liver to stop making glucose while a meal is being digested. Because the liver is not producing glucose and there is sufficient insulin to process the glucose from digestion, the blood glucose levels of healthy individuals remain relatively constant and their blood glucose levels do not become too high.
Diabetes is a disease characterized by abnormally high levels of blood glucose and inadequate levels of insulin. There are two major types of diabetes—Type 1 and Type 2. In Type 1 diabetes, the body produces no insulin. In the early stages of Type 2 diabetes, although the pancreas produces insulin, either the body does not produce the insulin at the right time or the body's cells ignore the insulin, a condition known as insulin resistance.
Even before any other symptoms are present, one of the first effects of Type 2 diabetes is the loss of the meal-induced first-phase insulin release. In the absence of the first-phase insulin release, the liver will not receive its signal to stop making glucose. As a result, the liver will continue to produce glucose at a time when the body begins to produce new glucose through the digestion of the meal. As a result, the blood glucose level of patients with diabetes goes too high after eating, a condition known as hyperglycemia. Hyperglycemia causes glucose to attach unnaturally to certain proteins in the blood, interfering with the proteins' ability to perform their normal function of maintaining the integrity of the small blood vessels. With hyperglycemia occurring after each meal, the tiny blood vessels eventually break down and leak. The long-term adverse effects of hyperglycemia include blindness, loss of kidney function, nerve damage and loss of sensation and poor circulation in the periphery, potentially requiring amputation of the extremities.
Between two and three hours after a meal, an untreated diabetic's blood glucose becomes so elevated that the pancreas receives a signal to secrete an inappropriately large amount of insulin. In a patient with early Type 2 diabetes, the pancreas can still respond and secrete a large amount of insulin. However, this occurs at the time when digestion is almost over and blood glucose levels should begin to fall. This inordinately large amount of insulin has two detrimental effects. First, it puts an undue extreme demand on an already compromised pancreas, which may lead to its more rapid deterioration and eventually render the pancreas unable to produce insulin. Second, too much insulin after digestion leads to fat storage and weight gain, which may further exacerbate the disease condition.
Because patients with Type 1 diabetes produce no insulin, the primary treatment for Type 1 diabetes is daily intensive insulin therapy. The treatment of Type 2 diabetes typically starts with management of diet and exercise. Although helpful in the short-run, treatment through diet and exercise alone is not an effective long-term solution for the vast majority of patients with Type 2 diabetes. When diet and exercise are no longer sufficient, treatment commences with various non-insulin oral medications. These oral medications act by increasing the amount of insulin produced by the pancreas, by increasing the sensitivity of insulin-sensitive cells, by reducing the glucose output of the liver or by some combination of these mechanisms. These treatments are limited in their ability to manage the disease effectively and generally have significant side effects, such as weight gain and hypertension. Because of the limitations of non-insulin treatments, many patients with Type 2 diabetes progress over time and eventually require insulin therapy to support their metabolism.
Insulin therapy has been used for more than 80 years to treat diabetes. Intensive insulin therapy for diabetes involves providing a basal insulin, ideally present at a uniform level in the blood over a 24 hour period, and a bolus or meal time (prandial) insulin to cover the added carbohydrate load from digestion concomitant with each meal.
In 1936, Hans Christian Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the “milt” or semen of river trout. The insulin was added to the protamine and the solution was brought to pH 7 for injection. In 1946, Nordisk Company was able to form crystals of protamine and insulin and marketed it in 1950 as NPH (“Neutral Protamine Hagedorn”) insulin. NPH insulin has the advantage that it can be mixed with an insulin that has a faster onset to compliment its longer lasting action.
In the 1950's and 1960's high concentrations of zinc (greater than 2% zinc bound to amorphous insulin) were used to stabilize precipitated insulin, creating a prolonged insulin effect. These formulations created the lente, semi-lente and ultra lente formulations of long acting insulin, intended for basal use (U.S. Pat. No. 3,102,077 to Christensen; U.S. Pat. No. 2,882,203 to Petersen). However, due to the unpredictability of the insulin release profile, these basal formulations have gradually been replaced by formulations providing a more “peakless” profile.
Until very recently, and in many places today, basal insulin is usually provided by the administration of two daily doses of NPH insulin, separated by 12 hours. A patient eating three meals a day and using NPH insulin as the basal insulin requires five injections per day, one with each of three meals and two NPH insulin injections, one in the morning and the other at bedtime. To reduce the number of injections the patient must take, the morning dose of NPH insulin has been combined with a short acting insulin, (recombinant human insulin) or a rapid acting insulin analog, such as lispro. A typical combination is a 70% NPH to 30% rapid acting insulin analog mixture. As a result, the patient can reduce the number of injections from five per day to four per day. See, e.g., Garber, Drugs, 66(1):31-49 (2006).
More recently insulin glargine, (trade name LANTUS®) a “very long-acting” insulin analog has become available. It starts to lower blood glucose slowly after injection and keeps working for up to 24 hours, with a range of 14-26 hours, depending on the patient' individual needs. It differs from human insulin by having a glycine instead of asparagine at position 21 and two arginines added to the carboxy-terminus of the beta-chain. Insulin glargine is formulated at pH 4, where it is completely water soluble. After subcutaneous or intramuscular injection, the pH increases, causing the drug to precipitate, with just a small amount remaining soluble. This ensures that small amounts of LANTUS® are released into the body continuously, giving a nearly peakless profile. LANTUS® consists of insulin glargine dissolved in a clear aqueous fluid (100 IU, 3.6378 mg insulin glargine, 30 micrograms zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water to 1 ml).
Rosenstock, et al. (Diabetes Care. 31(1):20-5 (2008)), reported that patients who took insulin glargine had a much lower risk of low blood glucose (hypoglycemia) than the patients who took NPH insulin because of the predictable insulin release. Insulin spikes in the plasma can lead to hypoglycemia. During the day hypoglycemia can result in loss of mental acuity, confusion, increased heart rate, hunger, sweating and faintness. At very low glucose levels, hypoglycemia can result in loss of consciousness, coma and even death. While sleeping, these symptoms are not evident, so the patient is not aware of the need to ingest food to increase the glucose levels in the blood. Therefore, the predictability of insulin release overnight is critical. According to the American Diabetes Association (ADA), insulin-using diabetic patients have on average 1.2 serious hypoglycemic events per year, many requiring hospital emergency room visits by the patients. Therefore, a reliable slow releasing insulin formulation is extremely important for treatment of diabetes.
It is therefore an object of the present invention to provide a stable basal insulin with extended release properties.